We have developed a new technique to better understand what happens to the microstructure inside a tablet during rapid disintegration.

Limitations of Disintegration Testing

In traditional disintegration testing it is difficult to establish any detailed insights into the mechanism of tablet disintegration as the test is merely designed to indicate the time it takes for a tablet or capsule to disintegrate completely, and this is defined as the state "in which any residue of the unit [...] is a soft mass having no palpably firm core". Based on the results of the disintegration test it is judged whether or not the dosage form meets the specification required by the respective pharmacopoeia e.g. for immediate release formulations. Apart from establishing the conformity with such official guidelines the disintegration test yields little additional information and is not very useful to guide rational formulation design.

{xtypo_quote_right}New insights for immediate release formulations and new opportunities for PAT measurement techniques{/xtypo_quote_right}

Fast and Non-destructive Imaging of Disintegration

Yassin et al. have introduced an alternative method based on terahertz pulsed imaging (TPI) to advance the understanding of how excipients, the dosage form microstructure and the testing conditions affect the disintegration behaviour in immediate release formulations [1]. The method allows for the first time to quantify the disintegration process on time-scales of seconds by measuring the ingress of the dissolution medium into a tablet with high precision and accuracy. Using this data the authors demonstrate that the disintegration process can be explained using theoretical models much like what is known for controlled release dosage forms. It is possible to investigate in detail how subtle changes in disintegrant concentration or the temperature of the dissolution medium affect the disintegration behaviour.

Figure 1: Disintegration process measured using TPI. The method can resolve both the swelling of the tablet as well as the ingress of the dissolution medium into the tablet.

Subtle Differences in Formulation have Profound Effects

A change in crosscarmellose sodium concentration from 2 to 5 wt% has a dramatic effect on the disintegration kinetics, particularly at a water temperature of 20°C. Here the disintegration time of the tablet is one order of magnitude faster at the higher concentration of superdisintegrant.

The study also highlights the enormous effect of the temperature of the dissolution medium on how rapidly a tablet disintegrates: by changing the temperature from 37°C to 20°C the disintegration time reduced from 25 to 5 seconds in a tablet containing 5% croscarmellose sodium (see Figure 2 below).

Figure 2: Disintegration characteristics of tablets made from MCC and superdisintegrant at different concentrations and water temperature (modified from [1]).

The new method is universally applicable to a wide range of formulations for dosage forms with disintegration times from seconds to hours.

PAT Measurements of Porosity – Non-destructive and Meaningful

In addition the paper highlights that measuring the tablet porosity instead of its hardness is potentially a much better PAT method compared to the time consuming and destructive weight/thickness/hardness testing.

It was previously demonstrated that terahertz spectroscopy is an excellent and very promising tool to non-destructively determine the bulk porosity of a tablet in a simple transmission or reflection experiment [2]. Yassin et al. show that such porosity measurements are very sensitive in resolving the disintegration performance of an actual tablet. Given that the terahertz measurements can be performed on millisecond timescales this technology could be developed into a powerful at-line/on-line or even in-line PAT technique.

Figure 3 (left): THz refractive index can be used as a PAT tool to measure the tablet bulk porosity (modified from [2]).

Background

Terahertz pulsed imaging (TPI) was first introduced in 2007 to non-destructively measure the coating thickness of pharmaceutical tablets. Ever since then, there has been a concerted research effort throughout the PSSRC to further develop and exploit this technique for improving the quality of pharmaceutical coatings and to shed light on the intricacies behind the pharmaceutical tablet coating process.

A notable example of previous work is the use of TPI to monitor the growth of the coating layer during the coating process as an offline technique [1]. The technology was further developed as an inline modality, where unlike the more established techniques such as near-infrared and Raman spectroscopy, TPI could measure coating thickness of individual tablets directly without chemometric models and was able resolve the tablet-to-table thickness distribution inside the coating drum during the coating process [2]. This makes the terahertz technique a unique tool to investigate the microstructure of pharmaceutical tablets as discussed in a previous research highlight.

Validation and Application

In TPI the only material dependent variable that needs to be calibrated in order to measure absolute film thickness is the refractive index of the coating material. The refractive index at terahertz frequencies is different to that at visible frequencies and while it is possible to measure it using terahertz spectroscopy it is important to validate these measurements using an independent technique. In an effort to further demonstrate the applicability of TPI, the method was validated with x-ray microtomography [3] to confirm the assumption that the refractive index is constant, within acceptable error, across the tablet surface for quantifying the absolute coating thickness (Figure 1).

TPI was also demonstrated to quantify active coating processes with active coatings up to 500 µm thick [4]. The applicability of TPI was further shown to work hand in hand with existing techniques, especially as a reference technique in the development of chemometric coating models for in-line Raman spectroscopy of process monitoring and quantification of functional coats [5].

In order to bring users up to speed when using TPI in the context of quantitative pharmaceutical tablet measurement and data analysis, a recent paper [6] presented an extensive discussion on the relevant parameters that need to be controlled so as to not fall into the trap of misinterpreting the TPI measurements. Of a particular mention in this context is the case where active coating is applied to tablets. Interestingly, the refractive index of the active coating was found to change in response to certain process conditions leading to measurement uncertainties when determining the absolute coating thickness. By comparing the content measurements as measured by an HPLC assay and the TPI coating thickness measurements it was possible to establish an excellent correlation between the TPI coating thickness measurement and the drug content in the coating (Figure 2).

Process Understanding

A high level of intra-tablet and inter-tablet coating uniformity are desired attributes in the pharmaceutical film coating process. This is especially the case for tablets receiving functional coats such as sustained release formulations, where a high level of coating variability can potentially undermine the efficacy of the eventual drug product. Even though these attributes are well sought after in the industry, achieving them realistically may prove to be rather difficult.

To date, only a handful of investigations have aimed to identify the process conditions that reliably lead to a reduction in coating thickness variability. TPI, owing to its relatively high spatial resolution, has shown to be a suitable tool for quantifying active coating thickness uniformity of tablets coated under varying process conditions [7, 8]. In particular, using design of experiments (DoE) covering a wide range of realistic coating process conditions for process parameters such as drum load, drum rotation speed, spray rate, spray pressure and coating duration, TPI was used to non-destructively identify and optimise the critical process parameters for an active coating process (Figure 3 and 4). Specifically, it was found that low drum load, high drum rotation speed and long coating durations are factors that could improve intra-tablet and inter-tablet uniformity. Even though a low spray rate was shown to be beneficial for inter-tablet coating uniformity, the same setting would be counter-productive in reducing the level of intra-tablet coating uniformity.

One immediately obvious advantage of the TPI technique for the analysis of active coating processes in this context is the speed and ease of measurement compared to an HPLC content assay: no sample preparation is required, no solvents are used and need to be disposed of and each measurement is completed in well under one hour.

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Outlook

In light of recent developments, TPI has further proven to be a robust technology in the field of pharmaceutics with particular advancements made in investigating active coating processes. While the relative immaturity and stability limitations of the technology are barriers for industry-wide adoption, TPI has shown tremendous potential in studying the coating uniformities non-destructively that otherwise would have been difficult to perform, if not impossible, with the existing popular techniques. Future implementations of the TPI as an in-line tool can effectively resolve the inter-tablet inhomogeneities during the coating operation as previously shown [2] and real-time information can be acquired for in-depth process understanding leading to greater control of the process for the production of higher quality dosage forms.

PSSRC Facilities

The group of Dr Axel Zeitler at Cambridge has extensive experience with terahertz technology. The group has a number of custom made THz spectrometers as well as its own commercial TPI coating imaging system (Teraview TPI imaga 2000) and complementing technology to investigate dosage form microstructure, such as a Skyscan X-ray microtomography system.

Professor Peter Kleinebudde’s group in Dusseldorf has a range of film coating equipment and process experience that can be used to simulate realistic process conditions during pharmaceutical film coating. In addition there is a wide range of expertise on film coating of tablets and pellets within the cluster in the centres in Copenhagen, Ghent and Lille.

Magnetic Resonance Imaging

The use of MRI as a powerful imaging and characterization modality in pharmaceutical dissolution research is now well established [1]. The non-invasive and non-destructive nature of MRI enables the investigation of structural, chemical and dynamical processes in many optically opaque systems at the microscopic level. Spatial maps of water penetration, tablet swelling and dissolution, as well as the mobilization and distribution of drug products can now be quantified and visualized [2,3]. In addition, the hydrodynamics within a USP recommended flow-through dissolution apparatus can also be visualized by MRI [4]. Such comprehensive information is essential in pharmaceutical research for: (i) the correct interpretation of conventional drug dissolution profiles and (ii) the optimal design (QbD) of controlled release formulations.

MRI Principle

Magnetic resonance images of a sample are reconstructed from a nuclear magnetic resonance (NMR) signal, which is generated by certain nuclei (most commonly 1H) when subjected to a strong external magnetic field, B0, (e.g. 9.4 Tesla) and subsequently irradiated with radio frequency pulses. A spatially encoded NMR signal, i.e. an image, is first generated by the application of RF pulses and additional much smaller magnitude magnetic field gradients. The spatial image can then be obtained via Fourier transformation of the raw data. Figure 1 depicts the set-up of a vertical MRI magnet and USP-IV dissolution cell.

By tailoring the timings of the radio frequency pulses and magnetic field gradients, the MR images can be weighted to show different information such as the chemical composition, spin-lattice relaxation time (T1), spin-spin relaxation time (T2), and molecular self-diffusion coefficient, as well as the velocity of flowing dissolution media within the dissolution apparatus.

The ‘quantitative’ nature of magnetic resonance is one of the defining beauties of MRI. The acquired signal, in theory, is proportional to the number of nuclei of interest in a particular sample. Thus MRI tells us ‘how much’ of a particular substance we have in a particular system [1-3,5]. For example, we can spatially map the concentration of water, or the API in a swollen gel layer (see Figure 2).

In addition to ‘how much’, MRI data can be also be acquired and manipulated to give quantitative information regarding ‘how fast’ the molecules of interest move [1-3,5]. For example, of particular interest within the pharmaceutical research community is being able to: (i) quantify the rate of ingress of dissolution media into swellable matrices and (ii) quantify the rate of formation and expansion of gel layers (see Figure 2).

{xtypo_quote_right}Quantitative MRI provides unique insight into the change in tablet microstructure during dissolution.{/xtypo_quote_right}

Hence by using the comprehensive MRI based information of the tablet swelling process during dissolution, it is inturn possible to evaluate the polymer structure quantitatively. For example, we have found two distinct regimes in the ‘gel’ region, namely the ‘swollen glassy layer’ (SGL) and the ‘gel layer’, based on the correlation between the water concentration and T2 obtained by MRI (see Figures 3 and 4). The temporal evolution of each component can thus be monitored accordingly (see Figure 5).

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The movie shows how the in-vitro T2-relaxation time maps can be used to follow the evolution of the gel and swollen glassy layers with time and highlights the quite different behaviour of the formulations chosen here.

Interpreting drug release profiles

The determination of the gel structure and the evolution of each component are essential pieces of information because the water ingress and polymer swelling directly affect the drug release process. In particular, the definition of swollen glassy layer and its separation from the gel layer are critical to aid our understanding of drug release, because the HPMC polymer chains start to relax in the SGL and create larger voids for the drug to diffuse through.

A case study is illustrated in Figure 6. Three grades of HPMC with different molecular weights (K100M > K15M > K4M) were compared as swelling excipients for the release of model drug ibuprofen (IBU). It is found that the release rate of IBU from K4M is the highest, while K15M and K100M have similar release profiles. Without the differentiation of the SGL from gel layer, the comparison of total gel region (SGL+ gel layer) shows that K4M has the largest swollen layer, which in theory results in the slowest release rate. However this is contrary to the observed cumulative drug release profile. With the evaluation of a separate SGL and gel layer, it is clearly seen that the SGL of K4M disappears fastest, indicating the drug becomes fully hydrated in the shortest time. Despite the fact that the IBU from the K4M sample has the thickest gel layer to diffuse through, it still releases the fastest. Thus, in this case, the rate determining step for release of IBU from HPMC matrix is controlled by the rate of HPMC hydration.

Future work

The majority of current MRI research studies in the pharmaceutical community acquire signals from water molecules and very few studies have investigated directly the behaviour of the APIs, since the 1H signal from API is normally obscured by the huge 1H signal associated with the water based dissolution medium [2]. We are currently exploring the 2D imaging of the API using the signatory atoms it possesses. Preliminary results indicate that MRI shows great potential in revealing the distribution and evolution of APIs under in vitro pharmacopeial dissolution conditions. The combination of NMR and MRI techniques applied to API and dissolution media can bring together the imaging results of both species, which will certainly result in a more comprehensive understanding of the controlled release systems.

PSSRC Facilities

The group of Professor Lynn Gladden and Dr Mick Mantle at the Magnetic Resonance Research Centre (MRRC), University of Cambridge. The MRRC acts as a focus for applications of magnetic resonance techniques in chemical engineering research in the UK. The main research interest is in understanding multi-component adsorption, diffusion and flow processes. These phenomena are particularly important in the controlled release of pharmaceuticals, one of the focus areas of the research at the MRRC. The centre has wide expertise in the study of diffusion processes into pharmaceutical matrices and coatings by magnetic resonance imaging (MRI). A number of research projects at the MRRC are in collaboration with major pharmaceutical companies.

Terahertz Pulsed Imaging

Since 2007 when terahertz pulsed imaging (TPI) was first developed to non-destructively measure the coating thickness of pharmaceutical tablets there has been intense research in the PSSRC into how this technique can help improve the quality of pharmaceutical coatings and thus make controlled release technology based on coatings of single dosage forms attractive to industry.

Measurement Principle

The measurement principle of TPI is very simple [1]: a pulse of THz radiation is focused on the surface of the coated tablet. Due to its ability to penetrate polymer materials a part of the THz pulse penetrates into the coated tablet while the remaining part of the pulse is reflected from the tablet surface due to the change in refractive index at the interface of air and coating surface. The part of the THz pulse that penetrated into the tablet undergoes subsequent reflections whenever others is a change in refractive index, such as at each interface between different coating layers. The measurement principle is similar to radar or ultrasound techniques.

The penetrative power together with the direct contrast mechanism due to the layer interface makes the TPI technique so powerful. There is no other technique on the market that can measure non-destructively at depth and resolve multiple layers at the same time without any need for chemometric calibration.

Off-line Analysis

By TPI it was possible to to reveal significant differences in coating thickness between the different surfaces of the same tablet as well as depending on the process conditions during which the tablets were coated [2]. With increasing process scale it was found that the release rate decreased for sustained-release coated tablets which was explained by the higher density of the coating layer, and thus lower diffusion coefficient, due to mechanical effects in the pilot scale coater compared to the lab scale coating process [3]. It was possible to directly correlate the TPI coating thickness measurements to the drug release rate from dissolution testing. This potentially means that for this type of coating it could be possible to predict the drug release profile of a coated tablet based on a TPI measurement of a coated tablet in applications such as real time release.

Using off-line measurements the TPI technology was used to investigate the coating process [4,5] and to carry out a detailed analysis into how coating weak spots affect the drug release [6].

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In-line Sensor Technology

Based on the potential of TPI for coating analysis a sensor was designed that was capable of in-line measurements of individual tablets within a perforated pan coater in real time under full production scale conditions [7]. The TPI approach is unique in that the sensor can directly measure the coating thickness distribution at any time point during the process. This is impossible with NIR or Raman process sensors as they are only capable of measuring a time or spatial average of the coating thickness based on chemometric models. In contrast, an individual TPI measurement takes less than 10 ms and no chemometric calibration is required.

{xtypo_quote_right}TPI is a very powerful tool to develop advanced process understanding{/xtypo_quote_right}

Process Understanding

Using a design of experiments covering a wide range of coating process conditions we have recently demonstrated how TPI can be used to identify and optimise the critical process parameters for an active coating process to achieve optimal uniformity in terms of the intra-tablet coating thickness, and hence content uniformity. Such information would be very difficult, if not impossible, to obtain with any of the other established analytical technologies. The process understanding that was developed based on the terahertz analysis can be used to explain and validate the reading from PAT sensors such as Raman process control probes.

Validation

Extensive work was carried out to validate the TPI method [8,9] as well as to use TPI to guide the development of chemometric coating models for NIR and Raman process sensors [10] as well as together with optical coherence tomography [11].

Outlook

We have demonstrated the huge potential of TPI for pharmaceutical coating analysis. It is a very attractive technology for industrial applications as well as research and development: it is fast, non-destructive, requires little calibration and can provide information on multiple coatings on curved surfaces that cannot be measured with any other technique. We are confident that TPI will establish itself as the standard analysis tool for coated solid dosage forms.

PSSRC Facilities

The group of Dr Axel Zeitler at Cambridge has extensive experience with THz technology. The group has a number of custom made THz spectrometers as well as its own commercial TPI coating imaging system (Teraview TPI imaga 2000) and complementing technology to investigate dosage form microstructure, such as a Skyscan X-ray microtomography system.

In addition there is a wide range of expertise on film coating of tablets and pellets within the cluster in the centres in Düsseldorf, Copenhagen, Ghent and Lille.

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Videos

http://www.youtube.com/watch?v=bBLt0mEVZCgTablet imaging using a TPI imaga 2000 (TeraView Ltd. Cambridge, UK) fully automated tablet imaging system. The video is edited and shows the scan under accelerated playback. The total acquisition time for an entire tablet is about 30-60 min depending on sample size and resolution.

http://www.youtube.com/watch?v=s88UjRiZwJQVideo of the virtual THz cross-section through the coating structure of a sugar coated pharmaceutical tablet. In this representation the surface of the tablet is projected into a plane and all the coating structure is plotted relative to the surface. This representation is similar to the B-scan representation in ultrasound analysis. Note the detailed structure that can be resolved from within the sugar coating as well as the density inhomogeneities within the tablet matrix. The coating layer is clearly much thicker in the centre of the tablet compared to the edges.

http://www.youtube.com/watch?v=L7W7SRSRtH03D reconstruction of a THz pulsed imaging dataset obtained from a tri-layered pharmaceutical tablet. The dataset was acquired in reflection. The green surface is the outer surface of the tablet while the purple layers represent the interfaces between the respective layers in the tri-layered tablet. Note the penetrative power of the THz pulse (penetration of > 3 mm into the tablet, THz pulse power < 5 μW).